Yang L, Wang Z, Wang B, Justice NJ, Zheng H.
Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity.
J Neurosci. 2009 Dec 16;29(50):15660-8.
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The current study by Yang et al. shows a novel physiological role for APP in the regulation of the L-type voltage-gated calcium channel specifically in GABAergic neurons. These results highlight APP—and APP fragments—as important regulators of synaptic function, and give new insight into the role of neuronal APP, as well as insight into how disrupted APP proteolysis could affect synaptic plasticity in Alzheimer disease. Interestingly, there are several parallels between APP deletion and reported effects of endogenously applied Aβ peptide—both appear to augment current through the L-type channel via post translational regulation of steady-state levels. Scragg et al., 2005 showed that Aβ could promote insertion or retention of L-type channels in the plasma membrane, while here, Yang et al. show that full-length APP and the L-type channel are associated, and they hypothesize that APP could be mediating trafficking of the channel from the plasma membrane, although in an Aβ-independent fashion. It is hence interesting that multiple APP fragments can specifically affect L-type calcium channel currents and steady-state levels, but in apparent opposing roles. Of note is the specificity of these effects of APP deletion to GABAergic neurons; future studies will no doubt be required to understand the special role that APP plays in these neuronal subtypes.
Scragg JL, Fearon IM, Boyle JP, Ball SG, Varadi G, Peers C.
Alzheimer's amyloid peptides mediate hypoxic up-regulation of L-type Ca2+ channels.
FASEB J. 2005 Jan;19(1):150-2.
The finding that APP depletion can result in aberrations in calcium-channel function and synaptic function is interesting for reasons beyond the "protein’s normal role in neurons." We reported a little over a year ago that APP is severely depleted in neuronal somata in a manner correlated with Alzheimer plaque pathology (Barger et al., 2008). The more advanced the pathology in a given region, the lower the expression of APP in the neurons; likewise, the closer the neurons were to plaques, the lower their expression. Analysis of mRNA indicated that this was not simply a reflection of increased processing/degradation of APP protein.
The basic finding—that AD pathology is associated with a decline in APP expression—runs contrary to what many have assumed: that Aβ accumulation in AD results, at least in part, from elevated levels of its precursor. Interestingly, we did find a gradual rise in APP levels with advancing age. Thus, the drop in APP appears to reflect something peculiar to the pathogenic process of Alzheimer disease.
Barger SW, Dewall KM, Liu L, Mrak RE, Griffin WS.
Relationships between expression of apolipoprotein E and beta-amyloid precursor protein are altered in proximity to Alzheimer beta-amyloid plaques: potential explanations from cell culture studies.
J Neuropathol Exp Neurol. 2008 Aug;67(8):773-83.
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